title: Amodiaquine analogues containing NO-donor substructures: synthesis and their preliminary evaluation as potential tools in the treatment of cerebral malaria.
abstract: The synthesis and physico-chemical properties of novel compounds obtained by conjugation of amodiaquine with moieties containing either furoxan or nitrooxy NO-donor substructures are described. The synthesised compounds were tested in vitro against both the chloroquine sensitive, D10 and the chloroquine resistant, W-2 strains of Plasmodium falciparum (P. falciparum). Most of the compounds showed an antiplasmodial activity comparable to that of the parent drug. By comparing the activities of simple related structures devoid of the ability to release NO, it appears that the contribution of NO to the antiplasmodial action in vitro is marginal. All the compounds were able to relax rat aorta strips with a NO-dependent mechanism, thus showing their capacity to release NO in the vessels. A preliminary in vivo study using Plasmodium berghei ANKA-infected mice showed a trend for prolonged survival of mice with cerebral malaria treated with compound 40, which is potent and fast amodiaquine-derived NO-donor, when compared with amodiaquine alone or with compound 31, a milder NO-donor. The two compounds showed in vivo antiplasmodial activity similar to that of amodiaquine.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125 Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Marta
authors.initials: M
authors.lastname: Giorgis
authors.forename: Cristina
authors.initials: C
authors.lastname: Aragno
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Yuri C
authors.initials: YC
authors.lastname: Martins
authors.forename: Leonardo J M
authors.initials: LJ
authors.lastname: Carvalho
mesh_terms: D000655:Amodiaquine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002627:Chemistry, Physical; D016779:Malaria, Cerebral / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D020030:Nitric Oxide Donors / Q000737:chemistry*; D010069:Oxadiazoles / Q000737:chemistry*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000981:Antiprotozoal Agents; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D000655:Amodiaquine